Diet, behavior and immunity across the lifespan

doi:10.1016/j.neubiorev.2014.12.009

Neuroscience & Biobehavioral Reviews

Volume 58, November 2015, Pages 46-62

https://doi.org/10.1016/j.neubiorev.2014.12.009 Get rights and content

Highlights

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Undernutrition and overnutrition, perinatally and throughout life, cause increased risk for obesity and metabolic disorders.
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Nutrition also influences adverse mental health outcomes.
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The immune system is critical in this programing, linking diet with long term health and behavioral outcomes.

Abstract

It is increasingly appreciated that perinatal events can set an organism on a life-long trajectory for either health or disease, resilience or risk. One early life variable that has proven critical for optimal development is the nutritional environment in which the organism develops. Extensive research has documented the effects of both undernutrition and overnutrition, with strong links evident for an increased risk for obesity and metabolic disorders, as well as adverse mental health outcomes. Recent work has highlighted a critical role of the immune system, in linking diet with long term health and behavioral outcomes. The present review will summarize the recent literature regarding the interactions of diet, immunity, and behavior.

Introduction

The incidence of obesity has now reached epidemic proportions within our society, with upwards of 50% of the population classified as overweight or obese in many developed countries (Colagiuri et al., 2010, Ogden et al., 2014). Dietary factors clearly play a significant role in contributing to this phenomenon. Obesity is also characterized by systemic and central inflammation that causes and contributes to excess fat deposition (De Souza et al., 2005, Gregor and Hotamisligil, 2011, Spencer, 2013a). This inflammatory profile leaves the individual highly susceptible to disease, particularly to those relevant to immune dysfunction, including diabetes, cancers, mood disorders, vascular dysfunction, and susceptibility to infection (Haslam and James, 2005, Noria and Grantcharov, 2013).

The developmental origins of health and disease (DOHAD) hypothesis suggests there are certain ‘critical windows’ throughout early life when aspects of physiology, including brain development, are particularly vulnerable to environmental influences. In utero development and early postnatal life are two of these. At these times, the nutritional environment can alter the ability of an organism to integrate metabolic and feeding information, thus predisposing the organism to excess weight gain long-term. Outside these critical windows, metabolic and feeding pathways are potentially less plastic, but can still be shaped by dietary influences. For instance, medium to long-term ‘dieting’ (calorie restriction) in adult life can improve health and lifespan, in part by altering the hypothalamic inflammatory milieu. This central immune profile is important in regulating hypothalamic pathways involved in feeding, and life-long alterations in cytokine balance can greatly influence how one processes nutritional information. Diet, and the associated changes in the immune profile are not only critical in programing metabolic and feeding-related information, but have significant influence extending beyond the hypothalamus and into brain regions governing executive function. As such, our diet can be incredibly important in establishing several aspects of our behavioral and immune profile across our lifespan (Fig. 1). In this review we will address these aspects of the importance of diet throughout life.

Section snippets

Prenatal dietary programing of behavior and immunity across the lifespan

Nutrition during gestation can have lifelong impacts on an individual's health and behavior. In this period of embryonic and fetal development the mother's nutrition, particularly as it relates to her body weight and metabolism, appears to be absolutely critical to the later life health of her offspring.

This concept was first appreciated when epidemiological studies examined the long-term health outcomes of individuals who were in utero during the Dutch Hunger Winter (1944–1945). The offspring

Neonatal nutrition programs physiology long-term

As discussed, prenatal life is clearly a time of significant vulnerability to long-term programing of health and disease. A second such critical window of vulnerability occurs in the days to weeks after birth (Spencer et al., 2006, Spencer and Tilbrook, 2011, Spencer, 2012). As such, the neonatal nutritional environment can have substantial long-term programing effects on an individual's feeding behavior, satiety signaling, and metabolism, and can play an important role in susceptibility to

Dietary influences on immune function in adulthood: Calorie restriction

As well as during the critical prenatal and perinatal periods, dietary influences during adulthood can have profound effects on immune functioning. For example, exposure to a calorie restricted diet during adulthood can alter a number of immune system processes. Calorie restriction (CR), which usually involves the reduction of daily food intake while maintaining dietary composition and avoiding malnutrition (Weindruch and Walford, 1988), is perhaps best known for extending mean and maximum

Cytokines and energy homeostasis

Prenatal and perinatal programing as well as dietary changes during adulthood can alter the inflammatory milieu, which can have consequences for the maintenance of energy and nutrient homeostasis throughout life. Indeed, the clinical observation that sickness is often associated with anorexia, loss of appetite, or even cachexia, was historically the main evidence that molecules of the immune system may be able to influence appetite and energy homeostasis. Three cytokines have been recognized as

Conclusions and perspectives

The literature presented herein reviews the powerful impact that diet and nutrition (and the subsequent physiological responses to diet) can have on physiology and behavior; in particular, highlighting a role for the immune system as a critical link between diet and health. There is a clear and profound impact of early life nutrition, both in utero and in the early postnatal period, on physiology, and as reviewed here, specifically on brain development. Hypothalamic systems that underlie

Acknowledgements

SJS: This work was supported by a Discovery Project Grant from the Australian Research Council (ARC; DP130100508), and a Project Grant from the National Health and Medical Research Council (NHMRC; APP1011274). SJS is an ARC Future Fellow (FT110100084) and an RMIT University VC Senior Research Fellow. TMR was supported by the NIH (MH087978). BC: This work was supported by National Institute of Health grant DK094026.

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Prenatal LPS exposure increases hippocampus IL-10 and prevents short-term memory loss in the male adolescent offspring of high-fat diet fed dams
2022, Physiology and Behavior
Lipopolysaccharide (LPS) tolerance can reduce the neuroinflammation caused by high fat maternal diets; however, there are no reports that have evaluated the effects of prenatal LPS exposure on the memories of the offspring of high-fat diet fed dams. This study evaluated the effects of prenatal LPS exposure on the inflammatory parameters and redox status in the brain, as well as the object recognition memory of adolescent offspring of Wistar rat dams that were treated with a high-fat diet during gestation and lactation. Female pregnant Wistar rats randomly received a standard diet (17.5% fat) or a high-fat diet (45.0% fat) during gestation and lactation. On gestation days 8, 10, and 12, half of the females in each group were intraperitoneally treated with LPS (0.1 mg.kg⁻¹). After weaning, the male offspring were placed in cages in standard conditions, and at 6 weeks old, animals underwent the novel object recognition test (for short- and long-term memory). The offspring of the high-fat diet fed dams showed increased hippocampus IL-6 levels (21-days-old) and impaired short-term memories. These effects were avoided in the offspring of high-fat diet fed dams submitted to prenatal LPS exposure, which showed greater hippocampus IL-10 levels (at 21- and 50-days-old), increased antioxidant activity (50-days-old) in the hippocampus and prefrontal cortex, without memory impairments (short- and long-term memory). IL-6 has been consistently implicated in memory deficits and as an endogenous mechanism for limiting plasticity, while IL-10 regulates glial activation and has a strong association with improvements in cognitive function. Prenatal LPS exposure preventing the increase of IL-6 in the hippocampus and the impairment to short-term object recognition memory caused by the high-fat maternal diet.
Youth diet quality and hazard of mood disorder in adolescence and adulthood among an Australian cohort
2020, Journal of Affective Disorders
Citation Excerpt :
There are several mechanisms by which diet in youth may influence long-term mental health outcomes. Firstly, poor diet may have long-term biological effects due to nutrient deficiencies in the case of undernutrition (such as iron or omega-3 fatty acids required to support neurological functioning), or inflammation or metabolic derangement in the case of overnutrition and excess energy intake (Hale et al., 2015). Secondly, food preferences and dietary behaviours are developed in youth, within the context of socioeconomic and sociocultural circumstance and shape long-term dietary preferences into adulthood, which may affect or mediate adult health (Mikkila et al., 2005).
Prospective studies on youth diet and mood disorders outcomes are limited. We examined if youth diet quality was associated with mood disorder onset over a 25-year follow-up period.
In 1985, Australian participants (aged 10–15 years) completed a 24-hour food record. A validated 100-point Dietary Guidelines Index (DGI) assessed diet quality. In 2009–11, 1005 participants (aged 33–41 years) completed the lifetime Composite International Diagnostic Interview for age of first DSM-IV defined mood disorder (depression or dysthymia). Cox proportional hazards regression estimated hazard of mood disorder during the 25-year follow-up according to baseline DGI score. Sensitivity analyses censored the study at 5, 10, and 15 years after baseline and used log binomial regression to estimate relative risk (RR). Covariates included baseline negative affect, BMI, academic performance, smoking, breakfast eating, physical activity, and socioeconomic status.
The mean(SD) youth DGI score was 45.0(11.5). A 10-point higher DGI was not associated with hazard of mood disorder onset over the 25-year follow-up (Hazard Ratio (HR):1.00; 95% Confidence Interval (CI):0.89–1.13). The only indication that higher DGI might be associated with lower risk of mood disorder was within the first 5 years after baseline and this was not statistically significant (RR=0.85; 95% CI:0.60–1.18).
Loss-to-follow-up. A single 24-hour food record may not represent usual diet.
Youth diet did not predict mood disorders in adulthood. The suggestions of a lower risk of mood disorder during late adolescence highlights that further prospective studies are needed.
Adolescent microglia play a role in executive function in male mice exposed to perinatal high fat diet
2020, Brain, Behavior, and Immunity
In humans, excessive gestational weight gain during pregnancy is associated with an increased risk for executive function deficits in the offspring. Our previous work has confirmed this finding in mice, as offspring from dams fed a 60% high fat (HF) diet during breeding, gestation, and lactation demonstrate impulsive-like behavior in the 5 choice serial reaction time task (5CSRTT). Because the prefrontal cortex (PFC), which plays a key role in executive function, undergoes substantial postnatal adolescent pruning and microglia are actively involved in synaptic refinement, we hypothesized that microglia may play a role in mediating changes in brain development after maternal HF diet, with a specific focus on microglial activity during adolescence. Therefore, we treated male and female offspring from HF or control diet (CD) dams with PLX3397-formulated diet (PLX) to ablate microglia during postnatal days 23–45. After PLX removal and microglial repopulation, adult mice underwent testing to evaluate executive function. Adolescent PLX treatment did increase the control male dropout rate in learning the basic FR1 task, but otherwise had a minimal effect on behavior in control offspring. In males, HF offspring learned faster and performed better on a simple operant task (fixed ratio 1) without an effect of PLX. However, in HF offspring this increase in FR1 responding was associated with more impulsive errors in the 5CSRTT while PLX eliminated this association and decreased impulsive errors specifically in HF offspring. This suggests that adolescent PLX treatment improves executive function and particularly impulsive behavior in adult male HF offspring, without an overall effect of perinatal diet. In females, maternal HF diet impaired reversal learning but PLX had no effect on performance. We then measured gene expression in adult male PFC, nucleus accumbens (NAC), and amygdala (AMG), examining targets related to synaptic function, reward, and inflammation. Maternal HF diet increased PFC synaptophysin and AMG psd95 expression. PFC synaptophysin expression was correlated with more impulsive errors in the 5CSRTT in the HF offspring only and PLX treatment eliminated this correlation. These data suggest that adolescent microglia may play a critical role in mediating executive function after perinatal high fat diet in males.
Neonatal overfeeding increases capacity for catecholamine biosynthesis from the adrenal gland acutely and long-term in the male rat
2018, Molecular and Cellular Endocrinology
Citation Excerpt :
LPS treatment (F(2,29) = 3.29, p = 0.051) significantly increased ERK1/2 phosphorylation, with no effects of neonatal overfeeding (Fig. 6B and C). Suboptimal early life diet leads to long-term programming of metabolic and neurobehavioural function, including increased responsivity to psychological and immune stress (reviewed in (Hale et al., 2015)). We have previously shown that neonatally overfed rats exhibit a prolonged rise in circulating corticosterone and increased PVN neuronal activation in response to an immune challenge (Cai et al., 2016; Clarke et al., 2012), due to a less efficient capacity of the adrenal cortex to respond to ACTH (Cai et al., 2016).
A poor nutritional environment during early development has long been known to increase disease susceptibility later in life. We have previously shown that rats that are overfed as neonates (i.e. suckled in small litters (4 pups) relative to control conditions (12 pups)) show dysregulated hypothalamic-pituitary-adrenal axis responses to immune stress in adulthood, particularly due to an altered capacity of the adrenal to respond to an immune challenge. Here we hypothesised that neonatal overfeeding similarly affects the sympathomedullary system, testing this by investigating the biochemical function of tyrosine hydroxylase (TH), the first rate-limiting enzyme in the catecholamine synthesis. We also examined changes in adrenal expression of the leptin receptor and in mitogen-activated protein kinase (MAPK) signalling. During the neonatal period, we saw age-dependent changes in TH activity and phosphorylation, with neonatal overfeeding stimulating increased adrenal TH specific activity at postnatal days 7 and 14, along with a compensatory reduction in total TH protein levels. This increased TH activity was maintained into adulthood where neonatally overfed rats exhibited increased adrenal responsiveness 30 min after an immune challenge with lipopolysaccharide, evident in a concomitant increase in TH protein levels and specific activity. Neonatal overfeeding significantly reduced the expression of the leptin receptor in neonatal adrenals at postnatal day 7 and in adult adrenals, but did not affect MAPK signalling. These data suggest neonatal overfeeding alters the capacity of the adrenal to synthesise catecholamines, both acutely and long term, and these effects may be independent of leptin signalling.
Hippocampal-dependent memory deficit induced by perinatal exposure to polutted eels in middle-aged offspring mice: Sex differential effects
2017, Toxicology Letters
Citation Excerpt :
Brain development trajectory may be incredibly influenced by early-life events including immune challenges (Bilbo and Schwarz, 2009; Marques et al., 2013; Spencer, 2013a). In addition to infections, maternal conditions including elevated body weight, obesity, unhealthy diet such as high-fat or polluted fish-containing diets, trauma or stress and diseases, such as diabetes may constitute factors favoring pro-inflammatory responses (Bolton and Bilbo, 2014; Hale et al., 2014; Marques et al., 2013; Soualeh et al., 2017; Spencer, 2013a,b). Such conditions result in an enhanced cytokine production, which may have maternal, placental, fetal and/or postnatal origin (Hagberg et al., 2015; Hale et al., 2014; Hava et al., 2006), mediating a bi-directional communication between the nervous and immune regulatory systems (ThyagaRajan and Priyanka, 2012; Wilson et al., 2002).
The effects of perinatal exposure to low, intermediate, or highly polluted eels on neonatal, postnatal, adult and middle-aged brain inflammation, and on cognitive performances of middle-aged offspring mice were compared to those of offspring controls. Inflammatory markers in microglia were assessed in offspring on the postnatal days–PNDs 1, 21, 100 and 330. Activated p38MAPK, ERK-1/2 and p65, and acetylcholine levels were assessed in the middle-aged hippocampus. Plasma myeloperoxidase and corticosterone levels were evaluated at PND 330. Learning and its retention, and working memory in middle-aged offspring were assessed using the Morris water maze, and Y-maze. Our results showed enhanced microglia production of inflammatory markers across the lifespan of male as well as female exposed offspring. Inflammation and increased p38 MAPK activation were detected in the exposed middle-aged hippocampus of both exposed sexes. Significant levels of MPO, but not corticosterone, were found in middle-aged males and females perinatally exposed to eels. However, decreases in ERK1/2 and p65 activation, and acetylcholine levels were only detected in female hippocampus exposed to either intermediately or highly polluted eels. Sex selective effects were also detected with regard to memory, the only altered cognitive function. Thus, middle-aged females, but not males, perinatally exposed to either intermediately or highly polluted eels take longer to locate the escape platform, spend considerably less time in the platform and perform less visit to the platform in the retention test. Our results suggest perinatal programming of hippocampal-dependent memory deficit by inflammation in middle-aged offspring, in sex and dose dependent manner.
Offspring neuroimmune consequences of maternal malnutrition: Potential mechanism for behavioral impairments that underlie metabolic and neurodevelopmental disorders
2017, Frontiers in Neuroendocrinology
Citation Excerpt :
Maternal malnutrition, either in the form of undernutrition or overnutrition, changes levels of neuroendocrine factors during sensitive developmental periods and increases the risk for obesity and metabolic disease (Hales and Barker, 2001; Sullivan et al., 2015). Maternal overnutrition and obesity are associated with increased leptin, glucose, and proinflammatory cytokines that directly transfer to the fetus and can alter fetal-derived neuroendocrine signals to promote obesity in the offspring (Hale et al., 2015; Ralevski and Horvath, 2015; Spencer, 2013a; Sullivan et al., 2015). Paradoxically, maternal undernutrition and protein restriction are also associated with increased leptin and insulin signaling and obesity in the offspring (Delahaye et al., 2008; Gardner et al., 2005; Hales and Barker, 2001; Ralevski and Horvath, 2015; Ravelli and Osmond, 1999; Ravelli et al., 1976; Roseboom et al., 2000).
Maternal malnutrition significantly increases offspring risk for both metabolic and neurodevelopmental disorders. Animal models of maternal malnutrition have identified behavioral changes in the adult offspring related to executive function and reward processing. Together, these changes in executive and reward-based behaviors likely contribute to the etiology of both metabolic and neurodevelopmental disorders associated with maternal malnutrition. Concomitant with the behavioral effects, maternal malnutrition alters offspring expression of reward-related molecules and inflammatory signals in brain pathways that control executive function and reward. Neuroimmune pathways and microglial interactions in these specific brain circuits, either in early development or later in adulthood, could directly contribute to the maternal malnutrition-induced behavioral phenotypes. Understanding these mechanisms will help advance treatment strategies for metabolic and neurodevelopmental disorders, especially noninvasive dietary supplementation interventions.

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¹: These authors contributed equally to this work.

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ReviewDiet, behavior and immunity across the lifespan

Highlights

Abstract

Introduction

Section snippets

Prenatal dietary programing of behavior and immunity across the lifespan

Neonatal nutrition programs physiology long-term

Dietary influences on immune function in adulthood: Calorie restriction

Cytokines and energy homeostasis

Conclusions and perspectives

Acknowledgements

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Brain Behav. Immun.

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Brain Behav. Immun.

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Brain Behav. Immun.

Brain Behav. Immun.

Cell Metab.

Placenta

Cell

J. Am. Diet. Assoc.

J. Biol. Chem.

Neuron

Am. J. Clin. Nutr.

Cell. Immunol.

Nutrition

Prostaglandins Leukot. Essent. Fatty Acids

J. Clin. Virol.

Cell Signal.

Vitam. Horm.

Lancet Infect. Dis.

Physiol. Behav.

Mol. Metab.

Clin. Immunol.

Transfer of proinflammatory cytokines across term placenta

Obstet. Gynecol.

Interleukin 18 in the CNS

J. Neuroinflammation

Oxidative stress and altered lipid homeostasis in the programming of offspring fatty liver by maternal obesity

Am. J. Physiol. Regul. Integr. Comp. Physiol.

Developmental programming in response to maternal overnutrition

Front Genet.

Fetomaternal immune cross-talk and its consequences for maternal and offspring's health

Nat. Med.

Developmental origins of obesity and the metabolic syndrome: the role of maternal obesity

Front. Horm. Res.

Relationships of plasma interleukin-18 concentrations to hyperhomocysteinemia and carotid intimal-media wall thickness in patients with type 2 diabetes

Diabetes Care

Maternal perinatal undernutrition attenuates T-cell function in adult male rat offspring

Cell Physiol. Biochem.

The developmental origins of chronic adult disease

Acta Paediatr. Suppl.

Adult consequences of fetal growth restriction

Clin. Obstet. Gynecol.

Recent advances in the relationship between obesity, inflammation, and insulin resistance

Eur. Cytokine Netw.

A newly defined interleukin-1?

Nature

Influence of obesity on clinical outcomes in hospitalized children: a systematic review

JAMA Pediatr.

Gestational and postnatal low protein diet alters insulin sensitivity in female rats

Exp. Biol. Med. (Maywood)

Adult-onset calorie restriction and fasting delay spontaneous tumorigenesis in p53-deficient mice

Carcinogenesis

Early-life programming of later-life brain and behavior: a critical role for the immune system

Front Behav. Neurosci.

Enduring consequences of maternal obesity for brain inflammation and behavior of offspring

FASEB J.

Mortality and morbidity in laboratory-maintained Rhesus monkeys and effects of long-term dietary restriction

J. Gerontol. A: Biol. Sci. Med. Sci.

Postnatal diet-induced obesity in rats upregulates systemic and adipose tissue glucocorticoid metabolism during development and in adulthood: its relationship with the metabolic syndrome

Diabetes

Catch-up growth of head circumference of very low birth weight, small for gestational age preterm infants and mental development to adulthood

J. Pediatr.

Signalling of toll-like receptors

Handb. Exp. Pharmacol.

Intrauterine effects of maternal prepregnancy overweight on child cognition and behavior in 2 cohorts

Review
Diet, behavior and immunity across the lifespan